The present invention pertains to moldings, especially biomedical moldings such as ophthalmic moldings, comprising certain radiation sensitive groups on their surface and to a process for attaching said moldings to living tissue, in particular to the eye as a corneal prosthesis.
It is known e.g. from WO 95/13764 to provide corneal prostheses being composed of porous polymeric material for correcting the optical properties of an eye or altering the appearance thereof. Corneal inlays are in general implanted into or onto the cornea of a mammal using surgical methods, for example by making an incision in the stromal tissue of the cornea to form a pocket into which the onlay is placed, and then closing the incision by suturing.
A more recent method involves removing the corneal epithelial cell layers of the cornea by scraping, placing a synthetic lenticule directly onto and in intimate contact with the corneal tissue and holding it in place for a period of time which is sufficient for the epithelial cells to recover, grow over the implant and thus fix it in a persistent manner. The initial temporary fixation of the onlay on the cornea is accomplished by the use of a biocompatible glue such as a commercially available collagen- or fibrin-based two components glue. However said glues have not yet proven satisfactory mainly because of severe handling problems. For example, the surgeon always has to mix the glue components prior to use. Once the premixing has taken place, only a limited time period is available for using the glue depending on the glue""s specific curing time; this puts time-pressure on the surgeon. Following the attachment of the onlay onto the cornea, excessive glue has to be removed carefully because otherwise cured glue residues may inhibit the overgrowth of epithelial cells over the onlay. Further disadvantages of the known glues concern, for example, an insufficient mechanical stability and duration. In view of these and other drawbacks, there is a need for improved methods and materials for a temporary fixation of a polymeric onlay on a cornea.
Surprisingly, it now has been found that biomedical moldings, in particular ophthalmic moldings such as corneal onlays, may be attached conveniently to living tissue if they comprise certain radiation sensitive groups covalently bound to their surface.
The present invention therefore in one aspect pertains to a biomedical molding comprising a non-biodegradable biocompatible organic polymer comprising attached to its surface radicals of formula 
wherein R1 is, for example, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, sulfo, nitro, trifluoromethyl or halogen such as, for example, fluorine or chlorine, m is an integer from 0 to 2, and
Z is a group which functions as a triggerable precursor for carbene, nitrene or benzhydrol formation.
Examples of suitable biocompatible organic polymers to which the radicals of formula (1) are attached are polyaddition and polycondensation polymers, for example polyurethanes, epoxy resins, polyethers, polyesters, polyamides or polyimides; polyolefins, for example polyacrylates, polymethacrylates, polystyrene, polyethylene or halogenated derivatives thereof, polyvinyl acetate or polyacrylonitrile; or elastomers, for example silicones, polybutadiene or polyisoprene.
A preferred group of organic polymers are those being conventionally used for the manufacture of biomedical devices, e.g. ophthalmic devices such as contact lenses, artificial cornea ot intraocular lenses, which are not hydrophilic per se. Such materials are known to the skilled artisan and may comprise for example polysiloxanes, perfluoroalkyl polyethers, fluorinated poly(meth)acrylates or equivalent fluorinated polymers derived e.g. from other polymerizable carboxylic acids, polyalkyl (meth)acrylates or equivalent alkylester polymers derived from other polymerizable carboxylic acids, polyolefines, or fluorinated polyolefines, such as polyvinylidene fluoride, fluorinated ethylene propylene, or tetrafluoroethylene, preferably in combination with specific dioxols, such as perfluoro-2,2-dimethyl-1,3-dioxol. Examples of suitable bulk materials are e.g. Lotrafilcon A, Neofocon, Pasifocon, Telefocon, Silafocon, Fluorsilfocon, Paflufocon, Silafocon, Elastofilcon, Fluorofocon or Teflon AF materials, such as Teflon AF 1600 or Teflon AF 2400 which are copolymers of about 63 to 73 mol % of perfluoro-2,2-dimethyl-1,3-dioxol and about 37 to 27 mol % of tetrafluoroethylene, or of about 80 to 90 mol % of perfluoro-2,2-dimethyl-1,3-dioxol and about 20 to 10 mol % of tetrafluoroethylene. A group of particularly preferred hydrophobic polymers are non-porous or particularly porous perfluoroalkyl polyether (PFPE) homo- or copolymers or perfluoroalkyl acrylates or methacrylates, for example those as disclosed in PCT applications WO 96/31546, WO 96/31548, WO 97/35906 or WO 00/15686.
Another preferred group of biocompatible organic polymers are those being conventionally used for the manufacture of biomedical devices, e.g. contact lenses, which are hydrophilic per se, since hydrophilic groups, e.g. carboxy, carbamoyl, sulfate, sulfonate, phosphate, amine, ammonium or hydroxy groups, are inherently present in the material. Such materials are known to the skilled artisan and comprise for example polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate (HEMA), polyvinyl pyrrolidone (PVP), polyacrylic acid, polymethacrylic acid, polyacrylamide, poly-N,N-dimethyl acrylamide (DMA), polyvinyl alcohol, copolymers for example from two or more monomers from the group hydroxyethyl acrylate, hydroxyethyl methacrylate, N-vinyl pyrrolidone, acrylic acid, methacrylic acid, acrylamide, N,N-dimethyl acrylamide, vinyl alcohol, vinyl acetate and the like, polyalkylene glycols such as polyethylene glycols, polypropylene glycols or polyethylene/polypropylene glycol block copolymers. Typical examples are e.g. Polymacon, Tefilcon, Methafilcon, Deltafilcon, Bufilcon, Phemfilcon, Ocufilcon, Focofilcon, Etafilcon, Hefilcon, Vifilcon, Tetrafilcon, Perfilcon, Droxifilcon, Dimefilcon, Isofilcon, Mafilcon, Nelfilcon or Atlafilcon.
Another group of preferred organic polymers are amphiphilic segmented copolymers comprising at least one hydrophobic segment and at least one hydrophilic segment which are linked through a direct bond or a bridge member. Examples are silicone hydrogels, for example those disclosed in PCT applications WO 96/31792 and WO 97/49740.
The form of the organic polymer may vary within wide limits. Examples are moldings of all kinds, for example tubes, films, membranes and in particular ophthalmic moldings, such as contact lenses, intraocular lenses or artificial cornea. Further examples of moldings are materials useful for example as wound healing dressings, eye bandages, materials for the sustained release of an active compound such as a drug delivery patch, moldings that can be used in surgery, such as heart valves, vascular grafts, catheters, artificial organs, encapsulated biologic implants, e.g. pancreatic islets, materials for prostheses such as bone substitutes, or moldings for diagnostics, membranes or biomedical instruments or apparatus.
Z in formula (1) is, for example, a group of formula 
wherein R3 is an electron-withdrawing substituent, for example, fluorinated C1-C6-alkyl, such as a radical xe2x80x94C2F5 or preferably a radical xe2x80x94CF3, R1xe2x80x2 independently has the meaning of R1, and
m1 independently has the meaning of m.
R1 and R1xe2x80x2 are each independently of the other preferably C1-C4-alkoxy, C1-C4-alkyl or sulfo.
The variable m is 1 or preferably 0. The variable m1 is preferably 0.
One group of suitable radicals of formula (1) are those wherein Z is a group 
and m is 0.
A further group of suitable radicals of formula (1) are those wherein Z is a group xe2x80x94N3, and m is 1 or preferably 0.
The radicals of formula (1) may be attached to the molding surface by any known linking group that is biomedically acceptable and especially ophthalmically acceptable. For example, the radicals of formula (1) may be attached directly to the molding surface by means of a functional group, for example by a functional group of formula
xe2x80x94C(O)xe2x80x94Xxe2x80x94xe2x80x83xe2x80x83(3a) or 
xe2x80x94X1xe2x80x94C(O)xe2x80x94xe2x80x83xe2x80x83(3b); or 
xe2x80x94X1xe2x80x94C(O)xe2x80x94Xxe2x80x94xe2x80x83xe2x80x83(3c); or 
xe2x80x94X1xe2x80x94C(S)xe2x80x94Xxe2x80x94xe2x80x83xe2x80x83(3d); 
wherein X and X, are each independently of the other a group xe2x80x94Oxe2x80x94 or xe2x80x94NR2xe2x80x94, wherein R2 is hydrogen or C1-C4-alkyl. X and X1 are each independently preferably a group xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94 and in particular a group xe2x80x94NHxe2x80x94 each.
A preferred direct linking group between the radical of formula (1) and the molding surface is of formula (3a), (3b) or (3c). The radicals of formulae (3a)-(3d) are in each case to be understood that the left bond is directed to the radical of formula (1), and the right bond is directed to the organic polymer surface.
A preferred embodiment of the invention thus relates to a biomedical molding comprising attached to its surface radicals of the formula 
wherein R1, m and Z are as defined above, and A is a radical of the formula (3a), (3b), (3c) or (3d) above. Preferably, Z is a group of formula 
m is 0, and A is a radical of formula (3a) above. In another preferred embodiment, Z is a group xe2x80x94N3, m is 1 or preferably 0 and A is a radical of formula (3b) or (3d), in particular (3b).
Biomedical moldings comprising attached to their surface radicals of the formula (1a) may be prepared, for example, by reacting a compound of formula 
wherein A* is a radical xe2x80x94X1H, xe2x80x94NCO, xe2x80x94NCS, xe2x80x94COOH or a carboxy derivative, for example an acid halide, optionally activated ester, or anhydride, and R1, Z, X1 and m are as defined above,
with a coreactive group of the molding surface, which may be, for example, a radical xe2x80x94XH, xe2x80x94NCO, xe2x80x94NCS, xe2x80x94COOH or a carboxy derivative, for example an acid halide, ester or anhydride.
For example, the reactions of a compound of formula (1xe2x80x2) having a carboxy, carboxylic acid halide group, preferably activated ester, acid anhydride, lactone, isocyanato or isothiocyanato group with an amino or hydroxy compound of the molding surface, or vice versa, are well-known in the art and may be carried out as described in textbooks of organic chemistry. For example, the reaction of an isocyanato or isothiocyanato derivative of formula (1xe2x80x2) with an amino- or hydroxy-compound of the molding surface may be carried out in an inert organic solvent such as an optionally halogenated hydrocarbon, for example petroleum ether, methylcyclohexane, toluene, chloroform, methylene chloride and the like, or an ether, for example diethyl ether, tetrahydrofurane, dioxane, or a more polar solvent such as DMSO, DMA, N-methylpyrrolidone or even a lower alcohol, at a temperature of from 0 to 100xc2x0 C., preferably from 0 to 50xc2x0 C. and particularly preferably at room temperature, optionally in the presence of a catalyst, for example a tertiary amine such as triethylamine or tri-n-butylamine, 1,4-diazabicyclooctane, or a tin compound such as dibutyltin dilaurate or tin dioctanoate. It is advantageous to carry out the above reactions under an inert atmosphere, for example under an nitrogen or argon atmosphere.
In case of a compound of formula (1xe2x80x2) or the molding surface carrying a carboxy anhydride group, the reaction of the carboxy anhydride with the molding surface or the compound of formula (1xe2x80x2) carrying an amino or hydroxy group may be carried out as described in organic textbooks, for example in an aprotic solvent, for example one of the above-mentioned aprotic solvents, at a temperature from room temperature to about 100xc2x0 C.
In case of a compound of formula (1xe2x80x2) or the molding surface carrying a carboxy group, the reaction of the carboxy group with the molding surface or the compound of formula (1xe2x80x2) carrying an amino or hydroxy group may be carried out under the conditions that are customary for ester or amide formation, for example in an aprotic medium at a temperature from about room temperature to about 100xc2x0 C. It is further preferred to carry out the esterification or amidation reaction in the presence of an activating agent, for example N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxy succinimide (NHS), sulfo-N-hydroxy succinimide or N,Nxe2x80x2-dicyclohexyl carbodiimide (DCC) or in the presence of an o-(benztriazole)-uronium salt such as o-(benztriazol-1-y-)-N,N,N,N-tetramethyluronium hexafluorophosphate. Most preferably, the carboxylic acid derivative of formula (1xe2x80x2) is previously converted to an activated ester using one of the above-mentioned activating agents, and the activated ester is then further reacted with the hydroxy or preferably amino groups of the surface.
The resulting modified biomedical moldings are advantageously purified before use, for example by washing or extraction in a suitable solvent.
The compounds of formula (1xe2x80x2) are known and partly commercially available or may be prepared according to known processes.
Suitable coreactive functional groups may be inherently (a priori) present at the molding surface to be modified. If the molding surface contains too few or no reactive groups, the material surface can be modified previously by methods known per se, for example plasma chemical methods (see, for example, WO 94/06485), or conventional functionalization with groups such as xe2x80x94OH, xe2x80x94NH2 or xe2x80x94CO2H produced.
Preferably, amino or hydroxy groups of the molding surface are reacted with a compound of formula (1xe2x80x2) having a coreactive carboxy, carboxylic acid anhydride, activated carboxylic acid ester, carboxylic acid halide, isocyanate or isothiocyanate group. According to an also preferred alternative, carboxy, activated carboxylic acid ester or carboxylic acid halide groups of the surface are reacted with a compound of formula (1xe2x80x2) having a coreactive amino or hydroxy group.
According to a further embodiment of the invention, the radicals of formula (1) are attached to the molding surface by means of a spacer group. Suitable spacer groups are, for example, of formula
xe2x80x94A1xe2x80x94C(O)xe2x80x94Xxe2x80x94xe2x80x83xe2x80x83(3e); or 
xe2x80x94A1xe2x80x94Xxe2x80x94C(O)xe2x80x94xe2x80x83xe2x80x83(3exe2x80x2) or 
xe2x80x94X1xe2x80x94C(O)xe2x80x94NHxe2x80x94Rxe2x80x94NHxe2x80x94C(O)xe2x80x94Xxe2x80x94xe2x80x83xe2x80x83(3f); or 
xe2x80x94X1xe2x80x94C(O)xe2x80x94A2xe2x80x94C(O)xe2x80x94Xxe2x80x94xe2x80x83xe2x80x83(3g); or 
xe2x80x94C(O)xe2x80x94X1xe2x80x94A3xe2x80x94Xxe2x80x94C(O)xe2x80x94xe2x80x83xe2x80x83(3h); or 
xe2x80x94C(O)xe2x80x94X1xe2x80x94A4xe2x80x94C(O)xe2x80x94Xxe2x80x94xe2x80x83xe2x80x83(3i); or 
xe2x80x94X1xe2x80x94C(O)xe2x80x94A5xe2x80x94Xxe2x80x94C(O)xe2x80x94xe2x80x83xe2x80x83(3j); 
wherein A1 is C1-C30-alkylene which may be interrupted by xe2x80x94Oxe2x80x94 except for C1-alkyl;
A2 is C1-C200-alkylene which may be interrupted by xe2x80x94Oxe2x80x94 except for C1-alkyl;
A3 is C2-C200-alkylene which may be interrupted by xe2x80x94O or xe2x80x94NHxe2x80x94;
A4 and A5 are each independently C2-C200-alkylene which may be interrupted by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NH(CO)xe2x80x94, xe2x80x94C(O)Oxe2x80x94 or xe2x80x94O(O)Cxe2x80x94;
R is linear or branched C1-C18-alkylene or unsubstituted or C1-C4-alkyl- or C1-C4-alkoxy-substituted C6-C10-arylene, C7-C18-aralkylene, C6-C10-arylene-C1-C2-alkylene-C6-C10-arylene, C3-C8-cycloalkylene, C3-C8-cycloalkylene-C1-C6-alkylene, C3-C8-cycloalkylene-C1-C2-alkylene-C3-C8-cycloalkylene or C1-C6-alkylene-C3-C8-cycloalkylene-C1-C6-alkylene; and X and X1 are as defined above.
The radicals of formulae (3e)-(3j) are in each case to be understood that the left bond is directed to the radical of formula (1) and the right bond is directed to the organic polymer surface.
A1 is preferably a branched or preferably linear C1-C12-alkylene radical or a radical xe2x80x94(CH2CH2O)1-5xe2x80x94CH2CH2xe2x80x94 and in particular linear C1-C4-alkyl or xe2x80x94(CH2CH2O)1-3xe2x80x94CH2CH2xe2x80x94.
R as alkylene in formula (3f) is preferably a linear or branched C3-C14alkylene radical, more preferably a linear or branched C4-C12alkylene radical and most preferably a linear or branched C6-C10alkylene radical.
When R is arylene, it is, for example, naphthylene or especially phenylene, each of which may be substituted, for example, by C1-C4-alkyl or by C1-C4-alkoxy. Preferably, R as arylene is 1,3- or 1,4-phenylene that is unsubstituted or substituted by C1-C4-alkyl or by C1-C4-alkoxy in the ortho-position to at least one linkage site.
R as aralkylene is preferably naphthylalkylene and most preferably phenylalkylene. The alkylene group in aralkylene contains preferably from 1 to 12, more preferably from 1 to 6 and most preferably from 1 to 4 carbon atoms. Most preferably, the alkylene group in aralkylene is methylene or ethylene.
When R is cycloalkylene, it is preferably C5-C6cycloalkylene and most preferably cyclo-hexylene that is unsubstituted or substituted by methyl.
When R is cycloalkylene-alkylene, it is preferably cyclopentylene-C1-C4-alkylene and especially cyclohexylene-C1-C4-alkylene, each unsubstituted or mono- or poly-substituted by C1-C4-alkyl, especially methyl. More preferably, the group cycloalkylene-alkylene is cyclohexylene-ethylene and, most preferably, cyclohexylene-methylene, each unsubstituted or substituted in the cyclohexylene radical by from 1 to 3 methyl groups.
When R is alkylene-cycloalkylene-alkylene, it is preferably C1-C4-alkylene-cyclopentylene-C1-C4-alkylene and especially C1-C4-alkylene-cyclohexylene-C1-C4-alkylene, each unsubstituted or mono- or poly-substituted by C1-C4-alkyl, especially methyl. More preferably, the group alkylene-cycloalkylene-alkylene is ethylene-cyclohexylene-ethylene and, most preferably, is methylene-cyclohexylene-methylene, each unsubstituted or substituted in the cyclohexylene radical by from 1 to 3 methyl groups.
R as C3-C8-cycloalkylene-C1-C2-alkylene-C3-C8-cycloalkylene or C6-C10-arylene-C1-C2-alkylene-C6-C10-arylene is preferably C5-C6-cycloalkylene-methylene-C5-C6-cycloalkylene or phenylene-methylene-phenylene, each of which may be unsubstituted or substituted in the cycloalkyl or phenyl ring by one or more methyl groups.
The radical R in formula (3f) has a symmetrical or, preferably, an asymmetrical structure.
A preferred group of spacer radicals comprises those of formula (3f), wherein R is linear or branched C6-C10alkylene; or cyclohexylene-methylene or cyclohexylene-methylene-cyclohexylene each unsubstituted or substituted in the cyclohexyl moiety by from 1 to 3 methyl groups.
The bivalent radical R in formula (3f) is derived preferably from a diisocyanate and most preferably from a diisocyanate selected from the group isophorone diisocyanate (IPDI), 4,4xe2x80x2-methylenebis(cyclohexyl isocyanate), 1,6-diisocyanato-2,2,4-trimethyl-n-hexane (TMDI), methylenebis(cyclohexyl-4-isocyanate) and hexamethylene diisocyanate (HMDI).
A2 in formula (3g) is preferably linear or branched C1-C24-alkylene or C4-C160-alkylene which is interrupted by xe2x80x94Oxe2x80x94, more preferably C1-C6-alkylene or C8-C60-alkyl which is interrupted by xe2x80x94Oxe2x80x94 and most preferably C1-C4-alkylene or -(alk)-Oxe2x80x94(CH2CH2O)8-25-(alk)-, wherein (alk) is, for example, C1-C6-alkyl, preferably C1-C4-alkyl, more preferably C1-C3-alkyl and in particular ethyl.
A3 is preferably linear or branched C1-C24-alkylene or C4-C160-alkylene which is interrupted by xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94, more preferably C1-C6-alkylene or C8-C60-alkyl which is interrupted by xe2x80x94Oxe2x80x94, and most preferably C1-C4-alkylene, or a radical -(alk)-Oxe2x80x94(CH2CH2O)8-25-(alk)-, wherein (alk is as defined above.
A4 as alkylene is, for example, branched or preferably linear C2-C24-alkylene, more preferably C2-C18-alkylene and in particular C4-C12-alkylene. An alkylene radical A4 which is interrupted by xe2x80x94Oxe2x80x94 is, for example, a radical xe2x80x94(CH2CHR5O)x-(alk)-, wherein (alk) is as defined above, R5 is hydrogen or methyl and x is from about 2 to about 99. A preferred alkylene radical A4 which is interrupted by xe2x80x94Oxe2x80x94 is a radical xe2x80x94(CH2CH2O)xxe2x80x94(CH2CH2)xe2x80x94, wherein x is from 4 to 80 and in particular from 8 to 80. An alkylene radical A4 which is interrupted by xe2x80x94C(O)NHxe2x80x94 is, for example, a polypeptide radical of formula xe2x80x94(CHR6xe2x80x94C(O)NH)txe2x80x94CHR6xe2x80x94, wherein R6 is hydrogen or C1-C4-alkyl which is unsubstituted or substituted by hydroxy, carboxy, carbamoyl, amino, phenyl, o-, m- or p-hydroxyphenyl, imidazolyl, indolyl or a radical xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH2 and t is an integer from about 2 to 80. An alkylene radical A4 which is interrupted by xe2x80x94C(O)Oxe2x80x94 or xe2x80x94OC(O)xe2x80x94 is, for example, a polyester radical. A preferred radical of formula (3i) corresponds to formula xe2x80x94C(O)Oxe2x80x94(CH2CH2O)8-80xe2x80x94CH2CH2xe2x80x94C(O)NHxe2x80x94 or xe2x80x94C(O)O-(alkxe2x80x2)-C(O)NHxe2x80x94 wherein (alkxe2x80x2) is branched or preferably linear C2-C18-alkylene.
A5 as alkylene is, for example, branched or preferably linear C2-C24-alkylene, more preferably C2-C18-alkylene and in particular C4-C12-alkylene. An alkylene radical A5 which is interrupted by xe2x80x94Oxe2x80x94 is, for example, a radical -(alk)-(OCHR4CH2)xxe2x80x94, wherein (alk) is as defined above, R4 is hydrogen or methyl and x is from about 2 to about 99. A preferred alkylene radical A5 which is interrupted by xe2x80x94Oxe2x80x94 is a radical xe2x80x94(CH2CH2)xe2x80x94(OCH2CH2)xxe2x80x94, wherein x is from 4 to 80 and in particular from 8 to 80. An alkylene radical A5 which is interrupted by xe2x80x94NHC(O)xe2x80x94 is, for example, a polypeptide radical of formula xe2x80x94CHR5xe2x80x94(NHC(O)xe2x80x94CHR5)txe2x80x94, wherein R5 is hydrogen or C1-C4-alkyl which is unsubstituted or substituted by hydroxy, carboxy, carbamoyl, amino, phenyl, o-, m- or p-hydroxyphenyl, imidazolyl, indolyl or a radical xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH2 and t is an integer from about 2 to 80. An alkylene radical A5 which is interrupted by xe2x80x94C(O)Oxe2x80x94 or xe2x80x94OC(O)xe2x80x94 is, for example, a polyester radical.
A further preferred embodiment of the invention thus relates to a biomedical molding comprising attached to their surface radicals of the formula 
wherein for R1, m and Z each the above given meanings and preferences apply, and Axe2x80x2 is a radical of the formula (3e), (3exe2x80x2), (3f), (3g), (3h), (3i) or (3j) above and preferably a radical of formula (3f), (3g) or (3i), wherein for the variables contained therein the above mentioned meanings and preferences apply.
Biomedical moldings comprising attached to their surface radicals of formula (1b) wherein Axe2x80x2is a radical of formula (3e) above may be prepared, for example, by reacting a compound of formula 
wherein A1, R1, Z and m are as defined above, or a carboxy derivative thereof, for example a halide, ester or anhydride thereof, with xe2x80x94XH groups of the molding surface, wherein X is as defined above. Moldings comprising attached to their surface radicals of formula (1b) wherein Axe2x80x2 is a radical of formula (3exe2x80x2) above may be prepared, for example, by reacting a compound of formula (1xe2x80x2) above, wherein A* is a radical xe2x80x94X1H, with carboxy groups or a derivative thereof of the molding surface.
Biomedical moldings comprising attached to their surface radicals of formula (1b) wherein Axe2x80x2 is a radical of formula (3f) or (3g) above may be prepared, for example, by reacting a compound of formula (1xe2x80x2) above, wherein A* is a radical xe2x80x94X1H, and xe2x80x94XH groups of the molding surface, wherein X and X1 are as defined above, in any order with a compound of formula ONCxe2x80x94Rxe2x80x94NCO wherein R is as defined above, or with a compound of formula HOOCxe2x80x94A3xe2x80x94COOH or an above mentioned carboxy derivative thereof, wherein A3 is as defined above.
Biomedical moldings comprising attached to their surface radicals of formula (1b) wherein Axe2x80x2 is a radical of formula (3h) above may be prepared, for example, by reacting a compound of formula (1xe2x80x2) above, wherein A* is a radical xe2x80x94COOH or an above mentioned carboxy derivative thereof, and xe2x80x94COOH groups or an above mentioned carboxy derivative thereof of the molding surface, in any order with a compound of formula X1Hxe2x80x94A3xe2x80x94XH wherein X and X1 are as defined above.
Biomedical moldings comprising attached to their surface radicals of formula (1b) wherein Axe2x80x2 is a radical of formula (3i) above may be prepared, for example, by reacting a compound of formula (1xe2x80x2) above, wherein A* is a radical xe2x80x94COOH or an above mentioned carboxy derivative thereof, and xe2x80x94XH groups of the molding surface, in any order with a compound of formula HX1xe2x80x94A4xe2x80x94COOH or an above mentioned carboxy derivative thereof, wherein A4, X and X1, are as defined above.
Biomedical moldings comprising attached to their surface radicals of formula (1b) wherein Axe2x80x2 is a radical of formula (3i) above may be prepared, for example, by reacting a compound of formula (1xe2x80x2) above, wherein A* is a radical xe2x80x94X1H, and xe2x80x94COOH groups or an above mentioned carboxy derivative thereof of the molding surface, in any order with a compound of formula HOOCxe2x80x94A5xe2x80x94XH wherein A5, X and X1, are as defined above.
The compounds of formula (1xe2x80x2) and (1xe2x80x3) as well as the compounds of formulae ONCxe2x80x94Rxe2x80x94NCO, HOOCxe2x80x94A3xe2x80x94COOH, X1Hxe2x80x94A3xe2x80x94XH, HX1xe2x80x94A4xe2x80x94COOH and HOOCxe2x80x94A5xe2x80x94XH are well known in the art and commercially available in part. In addition, the reactions between reactive groups of the molding surface, a suitable compound of formula (1xe2x80x2) or (1xe2x80x3) and optionally one of the above mentioned bifunctional compounds to yield a moldings surface comprising radicals of the formula (1b) may be carried out in each case under conditions that are customary for ester, amide, urethane or urea formation, for example as outlined above.
Throughout the application terms such as carboxy, carboxylic acid, xe2x80x94COOH, sulfo, xe2x80x94SO3H, amino, xe2x80x94NH2 and the like always include the free acid or amine as well as a suitable salt thereof, for example a biomedically or in particular occularly acceptable salt thereof such as, for example, a sodium, potassium, ammonium salt or the like (of an acid), or a hydrohalide such a hydrochloride (of an amine).
According to still another embodiment of the invention, the radiation sensitive radicals of formula (1) may be attached to the biomedical molding by a process comprising the steps of (i) providing the molding surface with reactive groups by a plasma induced polymerization of an ethylenically unsaturated compound carrying a reactive group; and (ii) reacting the reactive groups of the modified molding surface with a coreactive compound comprising a radical of formula (1). A suitable process for the plasma induced polymerization of functional monomers is described, for example, in WO 98/28026. Suitable functional monomers which may be used in this step are any polymerizable unsaturated compound which carries reactive groups and can be evaporated and introduced into a plasma generating apparatus to contact the material to be coated provided therein. Examples of reactive groups to be contemplated herein include isocyanate (xe2x80x94NCO), isothiocyanate (xe2x80x94NCS), epoxy, anhydride, azlactone and lactone (e.g. xcex2-, xcex3-, xcex4-lactone) groups. A suitable vinyl monomer having a reactive group in this context is, for example, a compound of formula 
wherein R6 is hydrogen, unsubstituted or hydroxy-substituted C1-C6-alkyl or phenyl,
R7 is hydrogen, C1-C4-alkyl or halogen,
R8 and R8xe2x80x2 are each an ethylenically unsaturated radical having from 2 to 6 C-atoms, or R8 and R8xe2x80x2 together form a bivalent radical xe2x80x94C(R7)xe2x95x90C(R7xe2x80x2)xe2x80x94 wherein R7 is as defined above and
R7xe2x80x2 independently has the meaning of R7, and
(Alk*) is C1-C6-alkylene, and (Alk**) is C2-C12-alkylene.
The following preferences apply to the variables contained in formulae (4a)-(4e):
R6 is preferably hydrogen or hydroxy-C1-C4-alkyl, in particular hydrogen or xcex2-hydroxyethyl.
R7 is preferably hydrogen or methyl.
R8 and R8xe2x80x2 are preferably each vinyl or 1-methylvinyl, or R8 and R8xe2x80x2 together form a radical xe2x80x94C(R7)xe2x95x90C(R7xe2x80x2)xe2x80x94 wherein R7 and R7xe2x80x2 are each independently hydrogen or methyl.
(Alk*) is preferably methylene, ethylene or 1,1-dimethyl-methylene, in particular a radical xe2x80x94CH2xe2x80x94 or xe2x80x94C(CH3)2xe2x80x94.
(Alk**) is preferably C2-C4-alkylene and in particular 1,2-ethylene.
Particularly preferred vinyl monomers having a reactive group are 2-isocyanatoethylmethacrylate (IEM), 2-vinyl-azlactone, 2-vinyl-4,4-dimethyl-azlactone, acrylic acid, methacrylic acid, acrylic anhydride, maleic acid anhydride, 2-hydroxyethylacrylate (HEA), 2-hydroxymethacrylate (HEMA), glycidylacrylate or glycidylmethacrylat.
Suitable coreactive compounds in step (ii) comprising a radical of formula (1) are, for example, of formula (1xe2x80x2) above, wherein A* is, for example, xe2x80x94X1H, xe2x80x94COOH or a carboxy derivative, for example an acid halide, ester or anhydride thereof, and R1, Z and m are as defined above.
Biomedical moldings according to the invention that comprise radicals of the formula (1) are radiation sensitive, that is to say upon irradiation, for example with UV or visible light, the molding surface is provided with highly reactive carbene, nitrene or benzhydrol radicals which may react with all kinds of organic material including synthetic and natural polymers with the formation of covalent xe2x80x94Cxe2x80x94Cxe2x80x94 or xe2x80x94Cxe2x80x94Nxe2x80x94Cxe2x80x94 bonds. Accordingly, the biomedical moldings of the invention may be attached chemically on virtually every organic material including living tissue which turn them into a valuable tool for surgery, particularly for ophthalmic surgery.
It is thus a particular object of the invention to provide a corneal onlay, comprising attached to its surface radicals of the formula (1). Said onlay may be composed of any of the known synthetic materials with the requisite mechanical properties, as mentioned above. The corneal onlay is adapted for epithelial recolonization, which means, that the polymeric material from which the onlay is formed does not inhibit cellular attachment or motility. The radicals of formula (1) are attached to the synthetic material making up the onlay as described above. According to one embodiment of the invention, only a part of the onlay, preferably the inner anterior surface only, is provided with radicals of formula (1) in order to fix it on the cornea. According to another embodiment, both the outer posterior and anterior surface of the onlay, are provided with radicals of formula (1). The provision of the posterior surface of the onlay with radiation sensitive radicals may serve to further modify the outer onlay surface, for example in order to facilitate cellular attachment as is hereinafter described.
The fixation of an corneal onlay according to the present invention on the cornea may be initiated, for example, by irradiation, particularly by irradiation with UV or visible light. Preferably, the cornea is previously prepared for the attachment of the onlay, for example by removing the epithelial cell layers of the cornea by scraping. In general, the onlay is placed in intimate contact with the corneal tissue and is then irradiated. Suitable light sources for the irradiation are known to the artisan and comprise for example mercury lamps, high pressure mercury lamps, xenon lamps, carbon arc lamps or sunlight. Sensitizers may be used to shift the irradiation wavelength. In addition, a suitable filter may be used to limit the irradiation to a specific wavelength range. Preferably, the onlay surface to which have been previously applied the compound(s) comprising radicals of formula (1) is irradiated with light of a wavelength xe2x89xa7300 nm, preferably from 350 to 400 nm. The time period of irradiation is not critical but is usually in the range of up to 30 minutes, preferably from 10 secondes to 10 minutes, and more preferably from 15 seconds to 5 minutes, and particularly preferably from 20 seconds to 1 minute.
One preferred method of implanting a corneal onlay onto a cornea thus comprises
(i) providing an onlay comprising groups of formula (1) at its anterior surface only;
(ii) placing the onlay in contact with the corneal tissue; and
(iii) irradiating the onlay whereby the onlay is fixed on the cornea.
Subsequent to the above fixation of the onlay on the cornea, the posterior surface of the implant may be coated with a tissue growth promoting compound as described hereinafter.
Another preferred method of implanting a corneal onlay onto a cornea comprises
(i) providing an onlay comprising groups of formula (1) at both its posterior and anterior surface,
(ii) placing the onlay in contact with the corneal tissue;
(iii) before or after step (ii) coating the posterior surface with one or more components which promote the growth of tissue adjacent to the implanted onlay, and
(iv) irradiating the onlay whereby the onlay is fixed on the cornea, and the tissue growth promoting compound is fixed on the posterior onlay surface.
Suitable tissue growth promoting compounds in both above mentioned methods are, for example, albumine, extracellular matrix (ECM), fibronectin, laminin, chondroitan sulfate, collagen, cell-attachment proteins, anti-gelatine factor, cold-insoluble globulin, chondronectin, epidermal growth factor, mussel adhesive protein, sialo proteins, thrombospondin, vitronectin, and various proteoglycans, and/or derivatives of the above or mixtures thereof. Preferred tissue growth promoting compounds are collagen, cell-attachment proteins or epidermal growth factor.
The biomedical moldings of the invention provide a new route towards implanting a corneal onlay onto a cornea which is easy to perform, does not affect the wearers vision, and is safe. In particular, a mechanical stable fixation of the implant on the cornea is obtained which lasts for a period of time sufficient for the epithelial cells to recover, grow over the implant and thus fix it in a persistant manner. The onlays are very easy to handle, since the use thereof does not involve, for example, a premixing of glue components or time pressure of the surgeon due to specific curing times of the glue components. In addition, no tedious removal of excess glue after fixing the onlay onto the cornea is necessary, and the previous problem of inhibition of overgrowth by glue residues does not exist. Moreover, the onlays of the invention may be stored conveniently for a long time, for example in form of a patch with cover foils protecting the surface(s). The onlay is then immediately ready for use, by just removing the cover foil(s) from the surface(s). All of the advantages mentioned above naturally apply not only to contact lenses but also to other biomedical moldings according to the invention as mentioned before.
In the examples, if not indicated otherwise, amounts are amounts by weight, temperatures are given in degrees Celsius.